Cycloaddition reactions of thiazolidine derivatives. An approach to the synthesis of new functionalized heterocyclic systems

Article abstract of DOI:10.1016/S0040-4039(01)01035-8

A one-pot procedure for the synthesis of two functionalized tricyclic systems having structures of benzo[g]isoquinoline-5,10-dione and dihydrothieno[2,3-b]naphto-4,9-dione (DTNQ) is described. These new series were synthesized from cycloaddition reactions

Full text of DOI:10.1016/S0040-4039(01)01035-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5755–5757
Cycloaddition reactions of thiazolidine derivatives. An approach
to the synthesis of new functionalized heterocyclic systems
Isabel M. Gomez-Monterrey, Pietro Campiglia, Orazio Mazzoni, Ettore Novellino and
M. Vittoria Diurno*
Dipartimento di Chimica Farmaceutica e Tossicologica, Universita` di Napoli ‘Federico II’, Via D. Montesano 49,
I-80131 Naples, Italy
Received 12 March 2001; accepted 8 June 2001
Abstract—A one-pot procedure for the synthesis of two functionalized tricyclic systems having structures of benzo[g]isoquinoline-
5,10-dione and dihydrothieno[2,3-b]naphto-4,9-dione (DTNQ) is described. These new series were synthesized from cycloaddition
reactions between naphthoquinone and arylthiazolidine derivatives, the latter acting, respectively, as highly reactive N-aryl-
idenedehydroalanine ethyl esters (2-AD) or as amino ester nucleophilic species. © 2001 Elsevier Science Ltd. All rights reserved.
Quinone-containing drugs such as adriamycin,
daunorubicin, and mitoxantrone, have been established
as one of the most effective classes of antitumor agents
in clinical use today, with broad application against a
number of malignant diseases.1 However, some severe
drawbacks in their use are the risk of dose-related
cardiotoxicity, and development of resistance toward
these compounds.2,3 The therapeutic potential for
modified aromatic quinones with improved pharmaco-
kinetic properties, potency or spectrum, and lower side
effects, prompted us to start a synthetic program
devoted to explore new quinone derivatives.
Our approach was based on the known ability of
quinone systems towards cycloaddition and nucleo-
philic addition reactions. In 1979, Ohler and Schmidt
reported4 the synthetic potential of thiazolidine deriva-
tives as precursors of highly reactive N-arylidenede-
hydroalanine ethyl esters (2-AD) and also, as masked
amino ester nucleophilic species. In the literature, the
addition of nucleophiles like amino acid esters5 as well
as Diels–Alder reactions of the appropriate 1-aza-6 or
2-azadienes supporting strongly electron-donating
groups7–9 to electron deficient quinones have been doc-
umented. Surprisingly, the cycloaddition reaction of
O
COOEt
2a (49%)
2b (37%)
N
2c (15-60%)
2d (6-69%)
O
O
R
COOEt
Ag2CO3, DBU
2
+
S
NH
CH3CN
O
R
O
O
S
S
1a, R= C6H5
1b, R= 4-CH3C6H4
1c, R= 4-ClC6H4
1d, R= 4-(CH3)2NC6H4
COOEt
N
COOEt
NH2
O
O
R
3'
3
Scheme 1.
Keywords: quinones; thiazolidines; non-proteinogenic amino acids; cycloadditions.
* Corresponding author. Tel.: (39)081678633; fax: (39)081678630; e-mail: diurno@unina.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01035-8

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I. M. Gomez-Monterrey et al. / Tetrahedron Letters 42 (2001) 5755–5757
iv
iii
v
v
5a
6a
O
O
O
(+)-3
(-)-3
R=H
R= CSNPh
S
S
ii
i
COOEt
NH-D-Phe-R
COOEt
iii
iv
6a
5b
R=H
NH2
O
R= CSNPh
4a,b R=Boc
3
Scheme 2. Reagents: (i) Boc-
D-Phe, HBTU, HoBT, DIEA, THF/DMF; (ii) HCl (g)/ether solution; (iii) chromatographic
separation; (iv) phenylisothiocyanate, Cl2CH2, D; (v) TFA in Cl2CH2.
quinone systems with substituted 2-azadienes support-
ing one or more electron-withdrawing appended
groups, remains unexplored.10 On this basis, we now
report an easy and versatile method directed towards
the synthesis, in a one-step reaction, of the new benzo-
deblocking and neutralization, preparative TLC of free
amine 5a,b with (90:10:1:1) CH2Cl2–MeOH–HAcO–
H2O yielded, isolated in decreasing order of Rf, the
diastereoisomers 5a and 5b. Then, reaction of these
compounds with benzylisothiocyanate gave the N-car-
bamoyl derivatives 6a (80%) and 6b (87%), respectively.
Edman degradation of the higher Rf 6a with trifluoro-
cetic acid led to enantiomer (+)3 [h]2D5=+21 (c 1.2,
MeOH) while the lower Rf diastereomer 6b provided
the enantiomer (−)3 [h]2D5=−19.9 (c 1.5, MeOH). To
date, unfortunately, the assignment of the absolute
configuration of the stereogenic center has not been
possible. Analytical and spectroscopic analysis of all
intermediate compounds was accorded with the struc-
ture proposed.
[g]isoquinoline-5,10-dione
b]naphtho-4,9-dione (DTNQ, 3) derivatives from naph-
thoquinone and arylthiazolidine derivatives.
2 and dihydrothieno[2,3-
Reaction of thiazolidines 1a–d, which were prepared, in
turn, from L-cystein ethyl ester and the corresponding
aldehydes, with 1 equiv. of silver carbonate and an
excess of naphthoquinone, under similar experimental
conditions11 from those reported by Gilchrist and co-
workers,10b gave mixtures of the fully aromatized Diels–
Alder cycloadducts 2a–c and the DTNQ derivative 3 in
different ratios and in 57–70% overall yield (Scheme 1).
In the case of thiazolidines 1c,d, the most stable inter-
In conclusion, the chemistry described here defines a
versatile strategy for the synthesis of functionalized
1-aryl-3-ethoxycarbonylbenzo[g]isoquinoline-5,10-dione
and 3-amino-3-ethoxy carbonyldihydrothieno[2,3-b]-
naphtho-4,9-dione. The cycloaddition reaction used
offers the possibility to prepare, in only a one-step
reaction, two adducts having different chemical struc-
tures. Ours preliminary results showed that the selectiv-
ity of the reaction should be tuneable by selecting the
reaction conditions. In addition, these chemotypes
retain the planarity, spatial and electronic characteris-
tics required for molecular recognition at the cellular
level, which seem to determine the antineoplastic and
antibacterial activities described for structurally related
analogues.15,16 The application of this method to the
preparation of new quinone analogues and different
chemical modification of the substituents in the amino
position of DTNQ is in progress.
1
mediates 3%c,d, can be detected by H NMR or even
isolated. Acid hydrolysis of these intermediates in 1N
HCl solution gave DTNQ as the hydrochloride salt. It
is interesting to note that when the reaction was carried
out with the thiazolidines 1c,d, under the conditions
described by Ohler and Schmidt, i.e. using 3 equiv. of
silver carbonate in the reaction mixture followed by
addition of DBU 30 minutes later, the cycloadducts 2c
(60%) and 2d (64%) were obtained as major products.
The structures of all new compounds were elucidated
from their analytical and spectroscopical data.12 Fur-
thermore, the structure of compound 3 was also con-
1
firmed through H NMR analysis of the more stable
intermediates 3%c,d. Thus, these compounds showed all
the signals corresponding to the two aromatic systems
and the azamethylene protons as single signals at 8.20
or 8.30 ppm. The chemical shifts of 2-H and 2%-H
protons of AB system are shifted 0.2–0.3 ppm to lower
fields in relation to those of compound 3.
References
As observed in the general reaction scheme, the new
and unusual a-amino ester 3 was obtained as a racemic
mixture of the (3S)- and (3R)-isomers, indicating that
during the formation of this product, the configura-
tional integrity of the C-4 thiazolidine ring is not pre-
served.13 The mixture of two enantiomers was resolved
following the Evans method for the resolution of
racemic amines14 (Scheme 2). Coupling of 3 with Boc-
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as determined by 1H NMR and HPLC. After Boc

I. M. Gomez-Monterrey et al. / Tetrahedron Letters 42 (2001) 5755–5757
5757
12. As an example, characterization data for 2c: yellow crys-
talline solid, mp 217–219°C; 1H NMR (500 MHz, CDCl3):
l 8.86 (s, 1H, 4-H); 8.34–8.32 and 8.19–8.17 (dd, 2H, 6-H
and 9-H); 7.87–7.85 (m, 2H, 7-H and 8-H); 7.51–7.45 (dd,
4H, aryl); 4.55–4.51 (q, 2H, CH2 ester); 1.48–1.45 (t, 3H,
CH3 ester). 13C NMR (125 MHz, CDCl3): l 182.1, 181.5
and 163.5 (CꢀO); 160.6 (1-C); 151.3 (3-C); 141.9 (10a-C);
138.1 (1%-C); 135.3 (4%-C); 135.2 (6-C); 134.4 (9-C); 133.9
and 132.1 (9a-C and 5a-C); 130.3 (2% and 6%-C); 128.3 (3%
and 5%-C); 127.5 and 127.0 (7-C and 8-C); 126.7 (4a-C);
119.9 (4-C); 62.8 (CH2 ester) and 14.2 (CH3 ester). Anal.
calcd for C22H14ClNO4: C, 67.43; H, 3.57; N, 3.56; Cl, 9.07.
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11. General procedure: The thiazolidines 1a–d (1–3 mmol)
were dissolved in dry acetonitrile and the naphthoquinone
(2 equiv.), silver carbonate (1 equiv. respect to thiazolidine)
and DBU in acetonitrile (0.2 equiv. respect to thiazolidine)
were added. After 12 h at room temperature, ether was
added, the mixture was filtered and the solvents were
evaporated. The residue of the reaction was dissolved in
chloroform and treated with 1N HCl solution for 1 h.
Then, chloroform and water were added, the organic phase
was washed with 1N HCl, water and dried with Na2SO4.
Removal of the solvent and flash chromatography of the
residues, using CHCl3 as eluant, yielded, in each case, the
corresponding Diels–Alder adducts 2a–c. In the other
hand, the collected acid acqueous phases were neutralized
with 10% NaHCO3 solution and the free amine 3 was
extracted with chloroform. Flash chromatography using a
gradient of 0–30% ethyl ether in CHCl3 gave the compound
3 as a orange oil: 11% from 1a, 20% from 1b, 45% from
1c, and 63% from 1d.
1H NMR (500 MHz, CDCl3): l 8.11–8.09 and 8.06–8.04
(dd, 2H, 8-H and 5-H); 7.76–7.69 (m, 2H, 6-H and 7-H);
4.31–4.27 (m, 2H, CH2 ester); 3.85–3.82 (d, 1H, 2-H,
J2,2%=12.3 Hz); 3.29–3.26 (d, 1H, 2%-H); 1.28–1.25 (m, 3H,
CH3 ester). 13C NMR (125 MHz, CDCl3): l 180.5, 178.7
and 172.0 (CꢀO); 155.1 (9a-C); 141.6 (3a-C); 132.9 (6-C);
131.8 (7-C); 131.1 (8a-C and 4a-C); 125.1 (8-C and 5-C);
72.2 (3-C); 62.6 (CH2 ester); 43.5 (2-C) and 13.9 (CH3
ester). Anal. calcd for C15H13NO4S: C, 59.04; H, 4.29; N,
4.62; S, 10.56. Found: C, 58.01; H, 4.60; N, 4.62; S, 10.21.
13. Detailed mechanism study will be submitted in a forthcom-
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